The development of molecular targeted therapy for advanced non-small cell lung cancer: latest evidence and updates

Abstract

The discovery of molecular targeted therapy has had a significant impact on the development of new treatment strategies for non-small cell lung cancer (NSCLC). Bevacizumab, an antiangiogenic agent targeting the vascular endothelial growth factor (VEGF), has improved overall survival in patients with non-squamous NSCLC. Additionally, many active driver mutations were identified in NSCLC, including mutations in the epidermal growth factor receptor (EGFR), and rearrangements in anaplastic lymphoma kinase (ALK), ROS1, RET and BRAF. First-line use of EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, is the standard treatment for patients with EGFR active mutations. Likewise, first-line use of ALK inhibitors such as crizotinib and alectinib is the standard treatment for patients with ALK rearrangements. Although majority of patients respond to treatment with TKIs, they eventually develop resistance to treatment within 12 months. Targeted therapeutic options for acquired resistance were developed against the reported resistance mechanisms. Furthermore, nivolumab, a fully human monoclonal antibody, is the first programmed death-1 (PD-1) inhibitor to be approved for the treatment of advanced NSCLCs. This agent has started a new era in the treatment of NSCLCs. Phase III trials comparing nivolumab and docetaxel in the treatment of relapsed NSCLC demonstrated a clear survival benefit by nivolumab. Further investigations for discovering specific biomarkers to facilitate the identification of a specific patient population that would benefit from this drug are warranted. The evidence and future perspective of targeted agents in the management of NSCLCs will be reviewed in this lecture.